oncology, management updates on metastatic cutaneous melanoma

1. By:Gebrekirstos,COR-II
Moderator:Dr Munir,Consultant Oncologist
AAU,CHS
October 29,2019
Case Presentation on Metastatic
Melanoma

2. Out line of presentation:
A) Case on the presentation
B) Investigation Modalities
C) Staging
D) Managements
E) Prognostic factors
F) Follow up
G) Case critics
H) References

3. B) Investigations
1)History –Hx of nevi,personal Hx of melanoma
2)Physical Exam-special attention to loco
regional area & LN drainage.
• complete dermatologic examination is
recommended for all pts with newly
diagnosed melanoma

4. B)Investigations…
3)Biopsy
• Pts presenting with a suspicious pigmented
lesion should undergo fullthickness biopsy
preferably with 1-2mm negative margins.
• Any met site should be confirmed
pathologically(FNAC,biopsy) except brain met

5. B) Investigations…
Biopsy
The procedure should be:
-full-thickness biopsy of the entire lesion
- include the most suspicious area of the lesion
-narrow margin of grossly normal skin (1 to 2 mm)
-include portion of edge (transitions) of lesion to normal skin
to enable assessment of the junctional change

6. B) Investigations…
Biopsy-types
-removing the entire lesion(excisional biopsy)-gold standard
-Portion of the lesion (incisional biopsy)
-punch biopsy
- shave biopsy

8. B) Investigations…
• Pathology report:
• NCCN Melanoma Panel recommend minimum
inclusion of:
-Breslow thickness
-ulceration status
-mitotic rate (#/mm2)
- deep and peripheral margin status (+ve or -ve)
- presence or absence of microsatellitosis
-pure desmoplasia if present
- total number of LNs examined & the presence or
absence of extranodal tumor extension

9. B)Investigations…
4)IHC staining for melanoma markers (S100,
HMB45, tyrosinase & MART-1/MelanA)
5) Gene mutation –stage IV-BRAF,KIT

10. B) Investigation Modalities…
6) Sentinel LN biopsy(SNBx)
• In the past, standard recommendation was to perform
ELNDs for intermediate thickness melanoma(1-4mm)
• Current retrospective & prospective studies failed to
show any significant survival advantage of routine ELND
• New procedure (intraoperative lymphatic mapping &
SNBx) developed for surgical staging of clinically LN-ve
melanomas (in early 1990s)
• LN met is associated with higher risk of systemic disease

11. B) Investigation Modalities…
6) Sentinel LN biopsy(SNBx)
• SNBx detection rate using:
- both blue dye and radiocolloid =99%
-blue dye alone =87% ,P < .0001.
• Rate of positive SNBx in most series (typically for
melanomas >1 mm) is 15-25%.

13. B) Investigation Modalities…
8) FNAC
• High index of
suspicion & liberal
use of FNA for
suspicious regional
nodes should be
encouraged.

14. B)Investigations…
• Stage I & II
– H & P
– Routine imaging/lab tests not recommended
– Imaging only to evaluate specific signs or symptoms
• Stage IIIA ( SLN +ve )
– Consider imaging for baseline staging ( category IIB)
– Imaging only to evaluate specific signs or symptoms
• Stage IIIB/C SLN +ve, III clinically +ve nodes, III clinical satellite or in tansit
– Imaging for baseline staging and to evaluate specific signs or symptoms ( CT,
PET or MRI )
• Stage IV
– Imaging for baseline staging and to evaluate specific signs or symptoms ( CT,
PET or MRI)
– LDH
– Testing for BRAF & other genetic analysis
• Stage IIIC & above
– Brian MRI as baseline

16. D)Management of melanoma
• For management purpose cutaneous
melanomas are categorized as follows:
I)Localized disease with no evidence of
metastases (stage I-II)
II)Regional disease (stage III)
III)Distant metastatic disease (stage IV)

17. Metastatic melanoma
• Most met occurs after an interval from their original management for
clinically localized disease
• Interval for detection of distant met is shorter in pts initially presented
with high-stage disease.
• 60-80% of 1st met are local/regional sites including regional nodes.
• Most common 1st sites of visceral met are lung(10%) &liver(10%)
• Other visceral sites of met are brain, GI tract(especially small bowel) &
adrenal gland.
• New active systemic therapies for advanced melanoma are changing the
pts prognosis.
• Without treatment, or treatment with ineffective therapies, stage IV
melanoma were reported to have:
- median survival of 12 months
- survivals of 6 -9 months for those who presented with visceral
metastatic

18. D)Management of metastatic melanoma
• Options:
1) Palliative surgery
2) Palliative RT
3) Immune therapy
- Cytotoxic T lymphocyte antigen-4 (CTL-4) antibody
- Programmed cell death protein 1 (PD-1) antibody
-High dose IL-2
-Adoptive cell transfer therapy(ACT)
4) Targeted therapy
-BRAF/MEK mutation inhibitors
-KIT mutation inhibitors (imatinib )
5) Cytotoxic therapy
6) Clinical trials

19. D.1) Surgery for Distant Metastases (Stage IV)
• Cases in Which the Benefit of Surgery Is Clear
• Anemia due to occult bleeding from intestinal metastasis
• Bowel obstruction due to small bowel metastasis
• Cutaneous or subcutaneous metastasis with ulceration, pain,
or impending ulceration
• Lymph node metastasis with neurologic symptoms
• Symptomatic brain metastasis
• Life-threatening hemorrhage from metastasis

20. D.2) Immune Checkpoint Inhibitors
• The immune system is capable of identifying &
destroying malignant cells, called immunosurveillance.
• Conditions or events that compromise the immune
system can lead to cancer cells escaping
immunosurveillance
• Immunotherapies augmente the immune response to
overcome immune evasion mechanisms of cancer cells

21. D.2) Immune Checkpoint Inhibitors
• CTLA-4 & PD-1 are 2 receptors on T cells that upon ligand
binding trigger a signaling cascade that inhibits cell
activation, limiting the immune response
• Antibodies against these receptor removing the
inhibition of T-cell activation &releasing the brake on the
immune response.
• And this was recently recognized by 2018 Nobel Prize
award in Medicine to James Allison and Tasuku Honjo
for their research on CTLA-4 and PD-1

23. D.2.1) Cytotoxic T lymphocyte antigen-4 (CTLA-4)
antibody
Ipilimumab
• monoclonal antibody against the immune checkpoint
receptor CTLA –4.
• Two phase III trials in pts with unresectable stage III/IV
melanoma support the use of ipilimumab .
• Results from these trials showed that ipilimumab improved
-response rates -OS
-response duration -PFS
• Most importantly, extended follow up showed that resulted in
long term survival(5 year OS):
- ipilimumab =18%
-dacarbazine)=9%

24. Ipilimumab +Dacarbazine vs Dacarbazine
502 pts untreated met
melanoma,
randomized in1:1 to
ipilimumab (10 mg /kg)
+ dacarbazine (850
mg/m2)
dacarbazine (850 mg/m2)
+placebo, given at weeks 1,
4, 7, and 10,
followed by dacarbazine
alone every 3 weeks
Pts with SD or
objective response
and no dose limiting
toxic effects received
ipilimumab or placebo
every 12 weeks
thereafter as
maintenance therapy
primary end point -OS

25. Ipilimumab +Dacarbazine vs Dacarbazine
Variable Ipilimumab +Dacarbazine Dacarbazine Remark
OS 11.2 months 9.1 months
1 yr survival 47.3% 36.3%
2 yr survival 28.5% 17.9%
3yr survival 20.8% 12.2% P<0.001
Grade 3/4 toxicity 56.3% 27.5% P<0.001
Conclusion
Ipilimumab (at a dose of 10 mg per kilogram) in
combination with dacarbazine
compared with dacarbazine plus placebo, improved
overall survival in patients with
previously untreated metastatic melanoma.

27. D.2.2)programmed cell death protein 1 (PD-1) antibody
• Nivolumab
• Checkmate 037 compared nivolumab versus
investigator’s choice chemotherapy in pts with
unresectable stage III/IV melanoma who had previously
progressed on:
- ipilimumab
- BRAFV600 ihibitors, in BRAF mutation +ve
• Over 70% of pts in this trial had received two or more
prior systemic therapies.
• Results show nivolumab improved RR & duration
compared with chemotherapy.

28. Nivolumab vs Dacarbazine (without BRAF Mutation)
418 pts untreated met
melanoma with out BRAF
mutation randomly assigned
to:
Nivolumab (3
mg/kg ) every
2weeks
Dacarbazine
(1000 mg/m2
every 3weeks).
primary end point=OS

29. Nivolumab vs Dacarbazine (without BRAF Mutation)
Variable Nivolumab Dacarbazine Remarks
1 yr survival 72.9% 42.1% P<0.001
median PFS 5.1 months 2.2 months P<0.001
objective response rate 40% 13.9% P<0.001
grade 3 or 4 11.7% 17.6%
CONCLUSIONS
Nivolumab was associated with significant improvements in OS
& PFS, as compared with dacarbazine, among previously
untreate patients who had metastatic melanoma without a BRAF
mutation.

30. H) Management

31. D.2) Immune Checkpoint Inhibitors
• The results of Checkmate 066 & 067 support &
recommended that nivolumab should be considered as
first-line therapy in pts with unresectable or metastatic
disease.

32. D.2.3) Anti-CTLA-4/Anti-PD-1 Combination Therapy
• CTLA-4 and PD-1 inhibitor combination therapies have
been investigated in a number of trials in unresectable
stage III/IV melanoma .
• There are ongoing clinical trials evaluating even lower
doses of ipilimumab in combinations in order to mitigate
the toxicity while still maintaining the synergy of the
combination.

33. D.2.3) Anti-CTLA-4/Anti-PD-1 Combination Therapy
• Among pts treated with nivolumab + ipilimumab
combination therapy, RR, PFS, and OS tend to increase
with increasing PD-L1 expression level
• But ,none of these analyses were able to identify PD-L1
expression threshold for selection of an anti-PD-1 agent.
• Nivolumab/ipilimumab combination improved RR &
outcomes compared with ipilimumab monotherapy for
all PD-L1 expression levels—including pts with very low
PD-L1 expression

34. Nivolumab + ipilimumab vs nivolumab
• 5-year survival outcomes reported
recently(update of survival outcomes from the
Checkmate 067 trial with a minimum of 5 years of
follow-up)
• 945 pts with unresectable ,previously not treated
stage III or IV melanoma in 1:1:1 ratio to:
-nivolumab alone
-nivolumab + ipilimumab
-ipilimumab alone
Primary end point=PFS & OS

35. At minimum of 60 months follow up
Variables Nivolumab + ipilimumab Nivolumab ipilimumab Remarks
Median OS 60 months 36.9months 19.9 months
5 yrs OS 52% 44% 26%
No sustained deterioration of health-related QOL
No new late toxic effects were noted.
5 yrs PFS 36% 29% 8%

38. Nivolumab + ipilimumab vs nivolumab
• CONCLUSIONS
• sustained long-term OS at 5 years was
observed in a greater percentage of pts
received nivolumab + ipilimumab or
nivolumab alone than pts received ipilimumab
alone, with no apparent loss of QOL.

39. D.3)BRAF-Targeted Therapies
• 50% met cutanous melanoma have activating mutation of
BRAF
• Most melanoma BRAF mutations occur at V600 (usually
V600E occasionally V600K)
• BRAF inhibitors shows clinical activity in met melanomas
with BRAF V600 mutation.
• Co-administration with MEK inhibitors potentiates the
effects
• FDA-approved :
-BRAF inhibitors= vemurafenib, dabrafenib and encorafenib
-MEK inhibitors=trametinib, cobimetinib, and binimetinib

40. Sequence of Immune Checkpoint Inhibitors
• Preliminary results from a randomized phase
II trial show ↑ toxicity but trends toward
improved RR and OS for pts treated with
nivolumab followed by ipilimumab compared
with pts who received these therapies in the
reverse order.

41. Sequence of Immune Checkpoint Inhibitors
• Given that responses to immune checkpoint inhibitors
can take longer to develop, BRAF-targeted therapy may
be preferred in cases where :
-symptomatic diseases
-rapidly progressing disease
-overall health of pt is deteriorating
• Other pts with asymptomatic metastatic melanoma may
be good candidates for immune checkpoint inhibitor
therapy.

42. Immune Checkpoint Inhibitor Administration
Immune Checkpoint Inhibitor Administration

43. Response assessment in immune therapy
• Main feature of therapy with anti–CTLA-4 antibodies is long
durability of tumor responses in pts with objective response
• Pts with met to lung & liver who initially received ipilimumab in
May of 2001,continues in response beyond 15 yrs
• So it is difficult to use RACIST criteria to asses responses b/c:
I)it can appear late after the therapy
II)can pass through a process of apparent clinical progression
(pseudo progression)
• For this reason we use alternative response assessment called
immune related response criteria
• Application of traditional RECIST criteria may lead to premature
discontinuation in a patient who will eventually respond to
treatment.

46. Toxicity of Immune Checkpoint Inhibitors
• are autoimmune in nature
• 3 most common AEs are:
1)Cutaneous toxicities (rash,pruritus,maculopapular rash &vitiligo),
2)Gastrointestinal toxicities (diarrhea/colitis)
3)Fatigue
• most common high-grade toxicities :
1)Endocrinopathies (adrenal insufficiency, hypo/hyperthyroidism)
2)pancreatitis (elevated lipase and amylase)
3) hepatic AEs (elevated ALT/AST, hepatitis)
• potentially life threatening high grade immune related toxicities:
1)Nephritis
2)Pneumonitis
3)myocarditis

47. H) Management

48. D.4) Cytotoxic Therapy
• Melanoma is relatively chemotherapy-refractory tumor.
• mechanisms of resistance not well known but likely :
- Naturally resistant to apoptotic death
- DNA repair enzymes
- Efflux pumps for xenobiotics -highly expressed in melanoma than other ca
Chemotherapy is considered a 3rd /4th line treatment option in melanoma after:
1)clinical trials
2immune therapy
3)BRAF-targeted therapy(if indicated)
• Common cytotoxic agents being used in patients with metastatic melanoma
include :
-single agents =dacarbazine,temozolomide , fotemustine & Nab-paclitaxel
-combination CT- cisplatin, vinblastine, and dacarbazine (CVD)
- carboplatin+paclitaxel
- Dartmouth regimen (cisplatin,carmustine, dacarbazine, &tamoxifen).

49. EORTC 18032
• Temozolomide is at least as effective as dacarbazine in
metastatic disease
• 859 stage IV melanoma pts were randomized to
receive:
- PO temozolomide150 mg/m2/day for 7 days Q2 wks
- IV dacarbazine 1000 mg/m2 Q3 wks
- Median OS-temozolomide= 9.1 months
-dacarbazine 9.4 months
Response rate -temozolomide =14.5%
-dacarbazine =9.8%

50. Brain met Rx
Current treatment recommendation in pts with brain met from melanoma:
• All symptomatic brain met corticostoid should be administered initially
• Good PS with no/minimal systemic met;& solitary brain met-resection/SRS
• unresectable lesion or ≥5 small lesions=SRS
• Pts on immune therapy who are responding extracranially -continued
immunotherapy during RT
• Pts on BRAF , discontinued while on irradiation
• Palliative WBRT/hospice for:
-poor PS
-diffuse systemic disease
-more than 5 bulky lesions
-progressed on systemic therapy

51. E)Prognostic Factors
• Breslow thickness(↑thickness,bad prognosis)
• Ulceration (+ve bad prognosis)
• Mitotic rate(High mitotic rate)
• ↑level of invasion (Clark level)
• LVI & PNI
• presence of microscopic satellite
• tumor location(extrimeties better, H& N,trunk badprognosis)
• Age(young age good prognosis)
• Sex(Female better)
• LN status & number of +ve LNs
• Histology types(NM→ALM→SSM→LMM)
• Site of metastasis(CNS& visceral)
• Growth patterns(VGP)
• LDH value in stage IV(↑)

52. F) Follow up

53. H) References